U.S. patent number 10,118,894 [Application Number 15/326,100] was granted by the patent office on 2018-11-06 for isoindolinone derivatives useful as antiviral agents.
This patent grant is currently assigned to ViiV HEALTHCARE UK LIMITED. The grantee listed for this patent is VIIV HEALTHCARE UK LIMITED. Invention is credited to Brian Alvin Johns, Emile Johann Velthuisen, Jason Gordon Weatherhead.
United States Patent |
10,118,894 |
Johns , et al. |
November 6, 2018 |
Isoindolinone derivatives useful as antiviral agents
Abstract
Compounds of Formula I are disclosed and methods of treating
viral infections with compositions comprising such compounds.
##STR00001##
Inventors: |
Johns; Brian Alvin (Research
Triangle Park, NC), Velthuisen; Emile Johann (Research
Triangle Park, NC), Weatherhead; Jason Gordon (Research
Triangle Park, NC) |
Applicant: |
Name |
City |
State |
Country |
Type |
VIIV HEALTHCARE UK LIMITED |
Brentford, Middlesex |
N/A |
GB |
|
|
Assignee: |
ViiV HEALTHCARE UK LIMITED
(Brentford, Middlesex, GB)
|
Family
ID: |
53718075 |
Appl.
No.: |
15/326,100 |
Filed: |
July 20, 2015 |
PCT
Filed: |
July 20, 2015 |
PCT No.: |
PCT/IB2015/055489 |
371(c)(1),(2),(4) Date: |
January 13, 2017 |
PCT
Pub. No.: |
WO2016/012930 |
PCT
Pub. Date: |
January 28, 2016 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20170204058 A1 |
Jul 20, 2017 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62027359 |
Jul 22, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
31/14 (20180101); C07D 405/04 (20130101); C07D
413/04 (20130101); A61P 31/18 (20180101); A61P
31/12 (20180101); C07D 401/04 (20130101); C07D
209/46 (20130101) |
Current International
Class: |
C07D
209/46 (20060101); C07D 401/04 (20060101); C07D
405/04 (20060101); C07D 413/04 (20060101) |
Foreign Patent Documents
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WO 2009/026248 |
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Feb 2009 |
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WO |
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WO 2013/016441 |
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Jan 2013 |
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WO |
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Other References
Chemical Abstract Registry No. 1260845-50-8, indexed in the
Registry File on STN CAS Online Jan. 27, 2011. cited by examiner
.
Jonas Demeulemeester, et al. Expert Opinion on Therapeutic Patents,
24 (6): 609-632 (Jun. 1, 2014), (International search report only).
cited by applicant.
|
Primary Examiner: Chen; Po-Chih
Attorney, Agent or Firm: Brink; Robert H. Gimmi; Edward R.
Majarian; William R.
Parent Case Text
This application is a .sctn. 371 of International Application No.
PCT/IB2015/055489, filed 20 Jul. 2015, which claims the benefit of
U.S. Provisional Application No. 62/027,359, filed 22 Jul. 2014.
Claims
What is claimed is:
1. A compound of Formula I: ##STR00031## or a pharmaceutically
acceptable salt thereof wherein: R.sup.1 is C.sub.1-6 alkyl;
R.sup.2 is C.sub.5-14aryl, C.sub.3-7cycloalkyl,
(C.sub.3-7)cycloalkenyl, (C.sub.2-9)heterocycle, or
(C.sub.2-9)heteroaryl, each of which is optionally substituted by
one to four substituents selected from halo, C.sub.1-6 alkyl,
C.sub.1-6 hetereoalkyl, or C.sub.1-6 alkylene or C.sub.1-6
hetereoalklylene wherein said C.sub.1-6alkylene or C.sub.1-6
hetereoalklylene are bonded to adjacent carbon atoms on said
C.sub.5-14 aryl, C.sub.3-7cycloalkyl,
(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.2-C.sub.9)heterocycle, or
(C.sub.2-C.sub.9)heteroaryl to form a ring, and wherein each
heterocycle, heteroaryl, heteroalkyl, and hetereoalkylene contains
one to three heteroatoms selected from S, N or O; L is a bond or
C.sub.1-3 alkylene: and R.sup.3 is H, C.sub.1-6 alkyl,
C.sub.5-14aryl, C.sub.3-7cycloalkyl, (C.sub.3-7)cycloalkenyl,
(C.sub.2-9)heterocycle, or (C.sub.2-9)heteroaryl, each of which is
optionally substituted by one to four substituents selected from
halo, or C.sub.1-6 alkyl, and wherein each heterocycle and
heteroaryl contains one to three heteroatoms selected from S, N or
O.
2. The compound or salt according to claim 1 wherein R.sup.1 is
t-butyl.
3. The compound or salt according to claim 1 wherein R.sup.2 is
optionally substituted phenyl or optionally substituted
cyclohexenyl.
4. The compound or salt according to claim 3 wherein R.sup.2 is
phenyl optionally substituted by one to four substituents selected
from fluorine, methyl, or --CH.sub.2CH.sub.2CH.sub.2O-- or
--NHCH.sub.2CH.sub.2O-- wherein said --CH.sub.2CH.sub.2CH.sub.2O--
or --NHCH.sub.2CH.sub.2O-- is bonded to adjacent carbon atoms on
said phenyl to form a bicyclic ring.
5. The compound or salt according to claim 1 wherein R.sup.3 is
phenyl.
6. The compound or salt according to claim 1 wherein the
stereochemistry on the carbon to which OR.sup.1 is bound is as
depicted below ##STR00032##
7. A pharmaceutical composition comprising a compound according to
claim 1 or a pharmaceutically acceptable salt thereof.
8. A method for treating a viral infection in a patient mediated at
least in part by a virus in the retrovirus family of viruses,
comprising administering to said patient a composition according to
claim 7.
9. The method of claim 8 wherein said viral infection is mediated
by HIV virus.
Description
FIELD OF THE INVENTION
The present invention relates to substituted isoindolinone
compounds, pharmaceutical compositions, and methods of use thereof
for (i) inhibiting HIV replication in a subject infected with HIV,
or (ii) treating a subject infected with HIV, by administering such
compounds.
FIELD OF THE INVENTION
The present invention relates to substituted isoindoline compounds,
pharmaceutical compositions, and methods of use thereof for (i)
inhibiting HIV replication in a subject infected with HIV, or (ii)
treating a subject infected with HIV, by administering such
compounds.
BACKGROUND OF THE INVENTION
Human immunodeficiency virus type 1 (HIV-1) leads to the
contraction of acquired immune deficiency disease (AIDS). The
number of cases of HIV continues to rise, and currently over
twenty-five million individuals worldwide suffer from the virus.
Presently, long-term suppression of viral replication with
antiretroviral drugs is the only option for treating HIV-1
infection. Indeed, the U.S. Food and Drug Administration has
approved twenty-five drugs over six different inhibitor classes,
which have been shown to greatly increase patient survival and
quality of life. However, additional therapies are still required
because of undesirable drug-drug interactions; drug-food
interactions; non-adherence to therapy; and drug resistance due to
mutation of the enzyme target.
Currently, almost all HIV positive patients are treated with
therapeutic regimens of antiretroviral drug combinations termed,
highly active antiretroviral therapy ("HAART"). However, HAART
therapies are often complex because a combination of different
drugs must be administered often daily to the patient to avoid the
rapid emergence of drug-resistant HIV-1 variants. Despite the
positive impact of HAART on patient survival, drug resistance can
still occur. The emergence of multidrug-resistant HIV-1 isolates
has serious clinical consequences and must be suppressed with a new
drug regimen, known as salvage therapy.
Current guidelines recommend that salvage therapy includes at least
two, and preferably three, fully active drugs. Typically,
first-line therapies combine three to four drugs targeting the
viral enzymes reverse transcriptase and protease. One option for
salvage therapy is to administer different combinations of drugs
from the same mechanistic class that remain active against the
resistant isolates. However, the options for this approach are
often limited, as resistant mutations frequently confer broad
cross-resistance to different drugs in the same class. Alternative
therapeutic strategies have recently become available with the
development of fusion, entry, and integrase inhibitors. However,
resistance to all three new drug classes has already been reported
both in the lab and in patients. Sustained successful treatment of
HIV-1-infected patients with antiretroviral drugs will therefore
require the continued development of new and improved drugs with
new targets and mechanisms of action.
For example, over the last decade HIV inhibitors have been reported
to target the protein-protein interaction between HIV-1 integrase
and Lens Epithelium Derived Growth Factor/p75 ("LEDGF"). LEDGF is a
cellular transcriptional cofactor of HIV-1 integrase that promotes
viral integration of reverse transcribed viral cDNA into the host
cell's genome by tethering the preintegration complex to the
chromatin. Because of its crucial role in the early steps of HIV
replication, the interaction between LEDGF and integrase represents
another attractive target for HIV drug therapy.
SUMMARY OF THE INVENTION
Briefly, in one aspect, the present invention discloses compounds
of Formula I:
##STR00002## wherein:
R.sup.1 is C.sub.1-6alkyl;
R.sup.2 is C.sub.5-14aryl, C.sub.3-7cycloalkyl,
(C.sub.3-7)cycloalkenyl, (C.sub.2-9)heterocycle, and
(C.sub.2-9)heteroaryl, each of which is optionally substituted by
one to four substituents selected from halo, C.sub.1-6alkyl,
C.sub.1-6hetereoalkyl, or C.sub.1-6alkylene or
C.sub.1-6hetereoalklylene wherein said C.sub.1-6alkylene or
C.sub.1-6hetereoalklylene are bonded to adjacent carbon atoms on
said of C.sub.5-14aryl, C.sub.3-7cycloalkyl,
(C.sub.3-C.sub.7)cycloalkenyl, (C.sub.2-C.sub.9)heterocycle or
(C.sub.2-C.sub.9)heteroaryl to form a ring, and wherein each
heterocycle, heteroaryl, heteroalkyl, and hetereoalkylene comprises
one to three heteroatoms selected from S, N or O;
L is a bond or C.sub.1-3alkylene:
R.sup.3 is H, C.sub.1-6alkyl, C.sub.5-14aryl, C.sub.3-7cycloalkyl,
(C.sub.3-7)cycloalkenyl, (C.sub.2-9)heterocycle, and
(C.sub.2-9)heteroaryl, each of which is optionally substituted by
one to four substituents selected from halo, C.sub.1-6alkyl, and
wherein each heterocycle and heteroaryl comprises one to three
heteroatoms selected from S, N or O;
In another aspect the present invention discloses pharmaceutically
acceptable salts of the compounds of Formula I.
In another aspect, the present invention discloses pharmaceutical
compositions comprising a compound of Formula I or a
pharmaceutically acceptable salt thereof.
In another aspect, the present invention discloses a method for
treating a viral infection in a patient mediated at least in part
by a virus in the retrovirus family of viruses, comprising
administering to said patient a composition comprising a compound
of Formula I, or a pharmaceutically acceptable salt thereof. In
some embodiments, the viral infection is mediated by the HIV
virus.
In another aspect, a particular embodiment of the present invention
provides a method of treating a subject infected with HIV
comprising administering to the subject a therapeutically effective
amount of a compound of Formula I, or a pharmaceutically acceptable
salt thereof.
In yet another aspect, a particular embodiment of the present
invention provides a method of inhibiting progression of HIV
infection in a subject at risk for infection with HIV comprising
administering to the subject a therapeutically effective amount of
a compound of Formula I, or a pharmaceutically acceptable salt
thereof. Those and other embodiments are further described in the
text that follows.
In accordance with another embodiment of the present invention,
there is provided a method for preventing or treating a viral
infection in a mammal mediated at least in part by a virus in the
retrovirus family of viruses which method comprises administering
to a mammal, that has been diagnosed with said viral infection or
is at risk of developing said viral infection, a compound as
defined in Formula I, wherein said virus is an HIV virus and
further comprising administration of a therapeutically effective
amount of one or more agents active against an HIV virus, wherein
said agent active against the HIV virus is selected from the group
consisting of Nucleotide reverse transcriptase inhibitors;
Non-nucleotide reverse transcriptase inhibitors; Protease
inhibitors; Entry, attachment and fusion inhibitors; Integrase
inhibitors; Maturation inhibitors; CXCR4 inhibitors; and CCR5
inhibitors.
DETAILED DESCRIPTION OF THE INVENTION
Preferably R.sup.1 is t-butyl.
Preferably R.sup.2 is optionally substituted phenyl or
cyclohexenyl. Most preferably, R.sup.2 is phenyl optionally
substituted by one to four substituents selected from fluorine,
methyl, or --CH.sub.2CH.sub.2CH.sub.2O-- or --NHCH.sub.2CH.sub.2O--
wherein said --CH.sub.2CH.sub.2CH.sub.2O-- or
--NHCH.sub.2CH.sub.2O-- is bonded to adjacent carbon atoms on said
phenyl to form a bicyclic ring.
Preferably R.sup.3 is phenyl.
Preferably the stereochemistry on the carbon to which OR.sup.1 is
bound is as depicted below.
##STR00003##
"Pharmaceutically acceptable salt" refers to pharmaceutically
acceptable salts derived from a variety of organic and inorganic
counter ions well known in the art and include, by way of example
only, sodium, potassium, calcium, magnesium, ammonium, and
tetraalkylammonium, and when the molecule contains a basic
functionality, salts of organic or inorganic acids, such as
hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,
and oxalate. Suitable salts include those described in P. Heinrich
Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts
Properties, Selection, and Use; 2002.
The method of treating or preventing metabolic disorders may
comprise administration of a compound or salt of this invention
alone as mono-therapy. The compounds and salts of this invention
may also be used in combination with other therapeutic agents.
Suitable agents for use in combination with the compounds and salts
of this invention include, for example, insulin sensitivity
enhancers, glucose absorption inhibitors, biquanides, insulin
secretion enhancers, or metformin.
EXAMPLES
The compounds of this invention may be made by a variety of
methods, including well-known standard synthetic methods.
Illustrative general synthetic methods are set out below and then
specific compounds of the invention are prepared in the working
examples.
##STR00004## ##STR00005##
Example 1:
2-(2-Benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindolin-5-yl)-2-(t-
ert-butoxy)acetic acid
##STR00006##
Step 1:
2-Benzyl-5-(benzyldimethylsilyl)-4,7-dimethylisoindolin-1-one
##STR00007##
N-Benzyl-N-(but-2-yn-1-yl)but-2-ynamide was prepared from the known
procedure as described in Org. Biomol. Chem., 2004, 2,
1287-1294.
Benzyl(ethynyl)dimethylsilane was prepared from the known procedure
as described in J. Am. Chem. Soc., 2005, 127, 3666-36667.
A solution of benzyl(ethynyl)dimethylsilane (5.2 g, 29.8 mmol) in
1,2-DCE (15 mL) was degassed with N.sub.2 for 5 min and treated
with Cp*ClRu(cod) (0.253 g, 0.666 mmol). To this was added degassed
solution of N-benzyl-N-(but-2-yn-1-yl)but-2-ynamide (1.5 g, 6.66
mmol) in 1,2-DCE (15 mL) dropwise over 10 min. After 1 h, the
reaction mixture was concentrated in vacuo and the residue purified
by silica gel chromatography (0-30% EtOAc/hexanes) to afford the
title compound as a yellow solid (1.66 g 62% yield; 4:1 mixture of
regioisomers). Major isomer--.sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta.=7.39-7.29 (m, 5H), 7.26 (s, 1H), 7.22-7.15 (m, 2H),
7.11-7.05 (m, 1H), 7.00-6.91 (m, 2H), 4.81 (s, 2H), 4.16-4.09 (m,
2H), 2.99-2.66 (m, 3H), 2.46-2.36 (m, 2H), 2.28-2.18 (m, 3H),
0.37-0.29 (m, 6H); LC/MS (m/z) ES.sup.+=400 (M+1)
Step 2: 2-benzyl-5-hydroxy-4,7-dimethylisoindolin-1-one
##STR00008##
An ice cold solution of
2-benzyl-5-(benzyldimethylsilyl)-4,7-dimethylisoindolin-1-one (1.66
g, 4.15 mmol) in Tetrahydrofuran (10 mL) was treated with TBAF
(16.62 mL, 16.62 mmol) dropwise over a 5 min period. After 10
additional min, methanol (30 mL), KHCO.sub.3 (0.832 g, 8.31 mmol)
and H.sub.2O.sub.2 (4.24 mL, 41.5 mmol) were added and the mixture
was warmed to ambient temperature. After 45 min, the reaction
mixture was partitioned between sat. aq. Na.sub.2S.sub.2O.sub.3 (1
mL) and EtOAc (3.times.10 mL). The organic layer was washed with
brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The
residue was purified by silica gel chromatography (0-3% MeOH/DCM)
to afford the title compound (0.67 g, 60%) as a white solid.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=7.37-7.28 (m, 6H), 6.67
(s, 1H), 5.82 (br. s., 1H), 4.77 (s, 2H), 4.10 (s, 2H), 2.66 (s,
3H), 2.08 (s, 3H); LC/MS (m/z) ES+=268 (M+1)
Step 3: 2-benzyl-6-bromo-5-hydroxy-4,7-dimethylisoindolin-1-one
##STR00009##
A suspension of 2-benzyl-5-hydroxy-4,7-dimethylisoindolin-1-one
(1.6 g, 6.0 mmol) and NaHCO.sub.3 (1.5 g, 18.0 mmol) in DCM (30 mL)
was treated with NBS (1.6 g, 9.0 mmol). After 20 min, the reaction
mixture was treated with saturated aqueous Na.sub.2S.sub.2O.sub.3
and the layers partitioned. The organic phase was washed with
water, dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. The residue was purified by silica gel chromatography
(0-100% EtOAc-hexanes) to afford the title compound as a white
solid (1.5 g, 70% yield). .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta.=7.29 (m, 5H), 6.01 (s, 1H), 4.75 (s, 2H), 4.05 (s, 2H),
2.81 (s, 3H), 2.15 (s, 3H); LC/MS (m/z) ES+=348 (M+2).
Step 4: 2-benzyl-5-hydroxy-4,7-dimethyl-6-vinylisoindolin-1-one
##STR00010##
A solution of
2-benzyl-6-bromo-5-hydroxy-4,7-dimethylisoindolin-1-one (300 mg,
0.867 mmol), potassium vinyltrifluoroborate (464 mg, 3.468 mmol)
and Na.sub.2CO.sub.3 (8.67 mL, 4.335 mmol, 2 M aqueous) in
1,4-dioxane (12 mL) was degassed with N.sub.2 for 5 min and treated
with Pd(dppf)Cl.sub.2.DCM (142 mg, 0.1734 mmol) and heated to
100.degree. C. After 3 h, the reaction mixture was cooled to
ambient temperature and filtered through a pad of Celite and the
solids washed with EtOAc. The filtrate was concentrated in vacuo
and the residue purified by silica gel chromatography (0-100%
EtOAc-hexanes) to afford the title compound (150 mg, 60% yield) as
a colorless oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=7.31
(m, 5H), 6.74 (m, 1H), 6.02 (s, 1H), 5.81 (dd, 1H), 5.55 (dd, 1H),
4.77 (s, 2H), 4.09 (s, 2H), 2.67 (s, 3H), 2.11 (s, 3H); LC/MS (m/z)
ES+=294 (M+H).
Step 5: 2-benzyl-4,7-dimethyl-1-oxo-6-vinylisoindolin-5-yl
trifluoromethanesulfonate
##STR00011##
A suspension of
2-benzyl-5-hydroxy-4,7-dimethyl-6-vinylisoindolin-1-one (150 mg,
0.614 mmol) and K.sub.2CO.sub.3 (85 mg, 0.614 mmol) in DMF (4 mL)
was treated with
1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide
(219 mg, 0.614 mmol). After 1 h, the reaction mixture was diluted
with EtOAc and poured into water. The layers were partitioned and
the organic phase washed with brine, dried (MgSO.sub.4), and
concentrated in vacuo. The residue was purified by silica gel
chromatography (0-100% EtOAc-hexanes) to afford the title compound
(191 mg, 88% yield) as a colorless oil. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.32 (m, 5H), 6.66 (m, 1H), 5.73 (dd, 1H),
5.45 (d, 1H), 4.78 (s, 2H), 4.13 (s, 2H), 2.74 (s, 3H), 2.25 (s,
3H); LC/MS (m/z) ES+=426 (M+H).
Step 6:
2-benzyl-4,7-dimethyl-5-(p-tolyl)-6-vinylisoindolin-1-one
##STR00012##
A solution of 2-benzyl-4,7-dimethyl-1-oxo-6-vinylisoindolin-5-yl
trifluoromethanesulfonate (175 mg, 0.412 mmol), p-tolylboronic acid
(224 mg, 1.648 mmol), and Na.sub.2CO.sub.3 (4 mL, 2.06 mmol, 2.0 M
aqueous) in DMF (5 mL) was degassed with N2 for 5 min, treated with
tetrakis(triphenylphosphine)palladium(0) (95 mg, 0.0824 mmol) and
heated to 80.degree. C. After 30 min, the reaction mixture was
cooled to ambient temperature, diluted with EtOAc and filtered
through a pad of Celite. The solids were washed with EtOAc and the
filtrate was washed with water, brine, dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by silica gel
chromatography (0-100% EtOAc-hexanes) to afford the title compound
(114 mg, 75% yield) as a colorless oil. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.31 (m, 5H), 7.18 (d, 2H), 6.94 (d, 2H),
6.32 (m, 1H), 5.30 (m, 1H), 5.04 (m, 1H), 4.81 (s, 2H), 4.12 (s,
2H), 2.80 (s, 3H), 2.38 (s, 3H), 1.88 (s, 3H); LC/MS (m/z) ES+=368
(M+H).
Steps 7:
2-benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindoline-5-carbaldehyde
##STR00013##
A solution of
2-benzyl-4,7-dimethyl-5-(p-tolyl)-6-vinylisoindolin-1-one (110 mg,
0.299 mmol) in THF/H.sub.2O (6 mL of a 3:1 solution) was treated
with potassium osmate dihydrate (44.1 mg, 0.120 mmol) and sodium
periodate (384 mg, 1.796 mmol). After 30 min, the reaction mixture
was treated with Na.sub.2S.sub.2O.sub.3 (6 mL, 10% aqueous
solution) and extracted with EtOAc. The organic layer was washed
with water, brine, dried (MgSO4), filtered and concentrated in
vacuo. The residue was purified by silica gel chromatography
(0-100% EtOAc-hexanes) to afford the title compound (42 mg, 38%) as
a white solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.79 (s,
1H), 7.33 (m, 5H), 7.26 (d, 2H), 7.05 (d, 2H), 4.82 (s, 2H), 4.18
(s, 2H), 3.06 (s, 3H), 2.42 (s, 3H), 1.96 (s, 3H); LC/MS (m/z)
ES+=370 (M+H).
Steps 8, 9, 10: Methyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindolin-5-yl)-2-(tert-butoxy-
)acetate
##STR00014##
An ice cold solution of
2-benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindoline-5-carbaldehyde
(42 mg, 0.114 mmol) in DCM (3 mL) was treated with zinc(II) iodide
(18 mg, 0.057 mmol, 0.5 equiv) and trimethylsilanecarbonitrile
(0.153 mL, 1.14 mmol, 10 equiv). After 10 min, the reaction mixture
was treated with water and the layers partitioned. The organic
layer was washed with brine, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to afford
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindolin-5-yl)-2-((trimethyls-
ilyl)oxy)acetonitrile (60 mg crude) that was used immediately
without further purification. LC/MS (m/z) ES+=469 (M+H).
An ice cold solution of
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindolin-5-yl)-2-((trimethyls-
ilyl)oxy)acetonitrile (60 mg, 0.129 mmol) in MeOH (40 mL) was
bubbled with HCl (g). After 30 min, the reaction mixture was
concentrated in vacuo and treated with HCl (aq.) (100 mL, 1.0 N)
and heated to 90.degree. C. After 1 h, the reaction mixture was
cooled to ambient temperature and extracted with EtOAc. The organic
phase was then washed with brine, dried (MgSO4), filtered and
concentrated in vacuo to afford methyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindolin-5-yl)-2-hydroxyaceta-
te (70 mg crude) that was used immediately without further
purification. LC/MS (m/z) ES+=430 (M+H).
A solution of
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindolin-5-yl)-2-hydroxyaceta-
te (70 mg, 0.163 mmol) in tert-butyl acetate (15 mL) was treated
with HClO.sub.4 (0.49 mL, 70%). After 15 min, the reaction mixture
was cooled to 0.degree. C. and the pH adjusted to 8 using aqueous
50% NaOH. The aqueous layer was extracted with EtOAc, and the
organic layer dried (MgSO.sub.4), filtered and concentrated in
vacuo. The residue was purified by silica gel chromatography
(0-100% EtOAc-hexanes) to afford the title compound (24 mg, 43%
over three steps) as a colorless oil. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.32 (m, 5H), 7.23 (m, 3H), 7.04 (d, 1H),
5.07 (s, 1H), 4.78 (s, 2H), 4.09 (s, 2H), 3.67 (s, 3H), 2.85 (s,
3H), 2.40 (s, 3H), 1.83 (s, 3H), 0.94 (s, 9H); LC/MS (m/z) ES+=486
(M+H).
Step 11:
(2-(2-Benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindolin-5-yl)-2-(te-
rt-butoxy)acetic acid
##STR00015##
A solution of Methyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindolin-5-yl)-2-(tert-butoxy-
)acetate (10 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was treated with
LiOH (0.52 mL, 0.52 mmol, 1.0 M aqueous) and heated to 80.degree.
C. After 6 h, the reaction mixture was concentrated in vacuo, and
partitioned between EtOAc and 1M HCl. The organic phase was washed
with brine, dried (MgSO.sub.4), filtered and concentrated in vacuo.
The residue was purified by reverse phase HPLC to afford the title
compound (6 mg, 62%) as a white solid. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.30 (m, 8H), 7.05 (d, 1H), 5.20 (s, 1H),
4.79 (d, 2H), 4.10 (d, 2H), 2.84 (s, 3H), 2.40 (s, 3H), 1.85 (s,
3H), 0.97 (s, 9H); LC/MS (m/z) ES+=472 (M+H).
Example 2:
(S)-(2-(2-Benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindolin-5-yl)-
-2-(tert-butoxy)acetic acid
##STR00016##
A sample of
2-(2-Benzyl-4,7-dimethyl-3-oxo-6-(p-tolyl)isoindolin-5-yl)-2-(tert-butoxy-
)acetic acid was purified using an S,S Whelk-O column (250.times.30
mm i.d., 5 .mu.m; Regis Technologies, Morton Grove, Ill.) under
supercritical conditions maintained at 40.degree. C., 140 bar, with
methanol modified CO.sub.2 (30% MeOH, 70% CO.sub.2) delivered at a
combined flow rate of 90 ml/min on a PIC prep SFC system (PIC
Solution; Avignon, France). Triggered collections were made using a
Knauer selectable wavelength UV-Vis dectector at 220 nm.
Chiral purity was determined by chiral analytical HPLC on a S,S
Whelk-O column (250.times.4.6 mm i.d., 5 .mu.m; RegisTechnologies,
Morton Grove, Ill.) under supercritical conditions maintained at
40.degree. C., 140 bar, with methanol modified CO.sub.2 (40% MeOH,
60% CO.sub.2) delivered at a combined flow rate of 2 ml/min on an
Aurora Fusion A5 Evolution SFC system (Agilent Technologies, Santa
Clara, Calif.) equipped with a DAD detector and monitored at 220
nm. Retention time of the title compound under these conditions was
5.67 min.
Example 3:
2-(2-benzyl-6-(4-chlorophenyl)-4,7-dimethyl-3-oxoisoindolin-5-y-
l)-2-(tert-butoxy)acetic acid
##STR00017##
The title compound was made in a similar manner as Example 1 except
using 4-chlorophenylboronic acid in Step 5. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta.=7.54-7.30 (m, 8H), 7.12 (br. s., 1H),
5.21-5.06 (m, 1H), 4.81 (s, 2H), 4.13 (d, J=2.0 Hz, 2H), 2.87 (br.
s., 3H), 1.86 (s, 3H), 1.11-0.98 (m, 9H); LC/MS (m/z) ES.sup.+=492
(M+1).
Example 4:
2-(2-benzyl-6-(chroman-6-yl)-4,7-dimethyl-3-oxoisoindolin-5-yl)-
-2-(tert-butoxy)acetic acid
##STR00018##
The title compound was made in a similar manner as Example 1 except
using 2-(chroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in
Step 5. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=7.39-7.29 (m,
5H), 7.17 (br. s., 1H), 6.92-6.77 (m, 2H), 5.27 (br. s., 1H),
4.89-4.75 (m, 2H), 4.24 (t, J=5.1 Hz, 2H), 4.12 (br. s., 2H),
2.91-2.75 (m, 5H), 2.11-2.00 (m, 2H), 1.90 (d, J=4.5 Hz, 3H), 1.01
(br. s., 9H); LC/MS (m/z) ES.sup.+=514 (M+1).
##STR00019## ##STR00020##
Example 5:
(S)-2-((M)-2-Benzyl-6-(8-fluoro-5-methylchroman-6-yl)-4,7-dimet-
hyl-3-oxoisoindolin-5-yl)-2-(tert-butoxy)acetic acid
##STR00021##
Step 1: Ethyl
2-(2-benzyl-6-hydroxy-4,7-dimethyl-3-oxoisoindolin-5-yl)-2-hydroxyacetate
##STR00022##
2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
was prepared from the known procedure described in
WO2009/062285.
An ice cold solution of
2-benzyl-5-hydroxy-4,7-dimethylisoindolin-1-one (1 g, 3.74 mmol) in
DCM (30 mL) was treated with TiCl.sub.4 (0.413 mL, 3.74 mmol).
After 5 min, ethyl 2-oxoacetate (0.742 mL, 3.74 mmol) was added.
After 5 h, the reaction mixture was cooled to 0.degree. C. and
treated with additional TiCl.sub.4 (0.207 mL, 1.87 mmol). After 18
h, the reaction mixture was poured into water and extracted with
EtOAc. The organic layer was washed with brine, dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo. The residue
was purified by silica gel chromatography (0-100% EtOAc-hexanes) to
afford the title compound (1.01 g, 73% yield) as a white foam.
.sup.1H NMR (400 MHz, CHLOROFORM-d)=8.22 (s, 1H), 7.38-7.28 (m,
5H), 5.73 (s, 1H), 4.85-4.67 (m, 2H), 4.30 (qd, J=7.1, 10.7 Hz,
1H), 4.18-4.11 (m, 1H), 4.05 (s, 2H), 3.84 (s, 1H), 2.84 (s, 3H),
2.08-2.04 (m, 3H), 1.22 (t, J=7.2 Hz, 3H); LC/MS (m/z) ES+=370
(M+1).
Step 2: Ethyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(((trifluoromethyl)sulfonyl)oxy)isoindol-
in-5-yl)-2-((triethylsilyl)oxy)acetate
##STR00023##
An ice cold solution of ethyl
2-(2-benzyl-6-hydroxy-4,7-dimethyl-3-oxoisoindolin-5-yl)-2-hydroxyacetate
(1 g, 2.71 mmol) in dichloromethane (20 mL) was treated with
imidazole (0.332 g, 4.87 mmol) and chlorotriethylsilane (0.545 mL,
3.25 mmol). After 30 min, the reaction mixture was poured into
water and the layers partitioned. The organic layer was washed with
1N HCl, brine, dried (Na.sub.2SO.sub.4), filtered and concentrated
in vacuo to afford methyl
2-(2-benzyl-6-hydroxy-4,7-dimethyl-3-oxoisoindolin-5-yl)-2-((triethylsily-
l)oxy)acetate as a yellow oil. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta.=8.72 (s, 1H), 7.37-7.28 (m, 5H), 5.68 (s, 1H), 4.76 (d,
J=2.0 Hz, 2H), 4.27-4.17 (m, 1H), 4.15-4.08 (m, 1H), 4.06 (d, J=2.0
Hz, 2H), 2.85 (s, 3H), 2.06 (s, 3H), 1.03-0.90 (m, 15H); LC/MS
(m/z) ES+=484 (M+1).
The residue was dissolved in DCM (30 mL), cooled to -78.degree. C.
and treated with triethylamine (0.874 mL, 6.27 mmol) and Tf.sub.2O
(0.457 mL, 2.71 mmol). After 1 h, the reaction mixture was poured
into water and the layers partitioned. The organic layer was washed
with 1 N HCl, sat. aq. NaHCO.sub.3, dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. The residue was purified by
silica gel chromatography (0-100% EtOAc-hexanes) to afford the
title compound (1.48 g, 89% yield) as a colorless gum. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta.=7.41-7.29 (m, 5H), 5.74 (s, 1H),
4.89-4.68 (m, 2H), 4.30-4.07 (m, 4H), 2.81 (s, 3H), 2.26 (s, 3H),
1.20 (t, J=7.2 Hz, 3H), 0.93-0.86 (m, 9H), 0.69-0.54 (m, 6H); LC/MS
(m/z) ES+=616 (M+1).
Step 3: Ethyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(((trifluoromethyl)sulfonyl)oxy)isoindol-
in-5-yl)-2-oxoacetate
##STR00024##
An ice cold solution of ethyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(((trifluoromethyl)sulfonyl)oxy)isoindol-
in-5-yl)-2-((triethylsilyl)oxy)acetate (1.46 g, 2.371 mmol) in
tetrahydrofuran (20 mL) was treated with 48% HF (5.0 mL, 138 mmol)
and warmed to ambient temperature. After 1.5 h, the reaction
mixture was diluted with EtOAc and quenched with the addition of
solid NaHCO.sub.3. The reaction mixture was filtered through a pad
of Celite and the filtrated was extracted with EtOAc. The combined
organic extracts were washed with brine, dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo to afford ethyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(((trifluoromethyl)sulfonyl)oxy)isoindol-
in-5-yl)-2-hydroxyacetate (1.1 g, 97%) as a white foam. 1H NMR (400
MHz, CHLOROFORM-d)=7.40-7.29 (m, 5H), 5.64 (d, J=2.5 Hz, 1H), 4.79
(d, J=3.0 Hz, 2H), 4.37-4.20 (m, 2H), 4.16 (s, 2H), 3.42 (d, J=2.8
Hz, 1H), 2.78 (s, 3H), 2.27 (s, 3H), 1.23 (t, J=7.2 Hz, 3H); LC/MS
(m/z) ES+=502 (M+1).
A solution of ethyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(((trifluoromethyl)sulfonyl)oxy)isoindol-
in-5-yl)-2-hydroxyacetate (1.1 g, 2.293 mmol) in DCM (20 mL) was
treated with Dess-Martin periodinane (1.207 g, 2.85 mmol). After 1
h, the reaction mixture was quenched with the addition of sat. aq.
Na.sub.2S.sub.2O.sub.3 and sat. aq. NaHCO.sub.3. After 15 min, the
reaction mixture was diluted with DCM and the layers partitioned.
The combined organic extracts were dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo to afford the title compound
(1.1 g, 93%) as a yellow foam. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta.=7.41-7.29 (m, 5H), 4.81 (s, 2H), 4.40 (q, J=7.1 Hz, 2H),
4.21 (s, 2H), 2.74 (s, 3H), 2.33-2.28 (m, 3H), 1.39 (t, J=7.2 Hz,
3H); LC/MS (m/z) ES+=500 (M+1).
Step 5: (S)-Ethyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(((trifluoromethyl)sulfonyl)oxy)isoindol-
in-5-yl)-2-hydroxyacetate
##STR00025##
A -45.degree. C. solution of ethyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(((trifluoromethyl)sulfonyl)oxy)isoindol-
in-5-yl)-2-oxoacetate (1.1 g, 2.102 mmol) and (R)-CBS (117 mg,
0.420 mmol) in toluene (15 mL) was treated dropwise with
catecholborane (4.20 mL, 4.20 mmol, 1.0 M in THF). The reaction
mixture was allowed to warm to -20.degree. C. over 1.5 h. The
reaction mixture was diluted with EtOAc and treated with 2M aqueous
Na.sub.2CO.sub.3. The reaction mixture was stirred vigorously for
30 min and the layers partitioned. The organic layer was washed
with sat. aq. NH.sub.4Cl, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography (0-100% EtOAc-hexanes) to afford the title compound
(950 mg, 90% yield) as a gummy solid. 1H NMR (400 MHz,
CHLOROFORM-d) .delta.=7.40-7.29 (m, 5H), 5.64 (d, J=2.5 Hz, 1H),
4.79 (d, J=1.8 Hz, 2H), 4.37-4.21 (m, 2H), 4.16 (s, 2H), 3.42 (d,
J=2.8 Hz, 1H), 2.79 (s, 3H), 2.28 (s, 3H), 1.24 (t, J=7.0 Hz, 3H);
LC/MS (m/z) ES+=502 (M+1).
Step 6: (S)-Ethyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(((trifluoromethyl)sulfonyl)oxy)isoindol-
in-5-yl)-2-(tert-butoxy)acetate
##STR00026##
Step 7: (S)-Ethyl
2-((M)-2-benzyl-6-(8-fluoro-5-methylchroman-6-yl)-4,7-dimethyl-3-oxoisoin-
dolin-5-yl)-2-(tert-butoxy)acetate
##STR00027##
A solution of (S)-Methyl
2-(2-benzyl-4,7-dimethyl-3-oxo-6-(((trifluoromethyl)sulfonyl)oxy)isoindol-
in-5-yl)-2-(tert-butoxy)acetate (120 mg, 0.215 mmol),
2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(81.73 mg, 0.279 mmol), and cesium fluoride (130.7 mg, 0.86 mmol)
in DME (5 mL) was degassed with N.sub.2 for 5 min, treated with
Sphos palladacycle (49.11 mg, 0.065 mmol) and irradiated in the
microwave for 40 min at 130.degree. C. The reaction mixture was
diluted with EtOAc, washed with sat. aq. NaHCO3, brine, dried
(Na2SO4), filtered and concentrated in vacuo. The residue was
purified using silica gel chromatography (0-50% EtOAc-hexanes) to
afford the title compound (30 mg, 24%) as a white solid. .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta.=7.37-7.28 (m, 5H), 6.62 (d,
J=11.3 Hz, 1H), 5.04 (s, 1H), 4.80 (s, 2H), 4.28 (t, J=5.1 Hz, 2H),
4.13-4.04 (m, 4H), 2.93 (s, 3H), 2.70 (d, J=4.8 Hz, 2H), 2.14 (d,
J=5.3 Hz, 2H), 1.79 (s, 3H), 1.75 (s, 3H), 1.17 (t, J=7.2 Hz, 3H),
1.10 (s, 9H); LC/MS (m/z) ES+=574 (M+1).
Step 8:
(S)-2-((M)-2-benzyl-6-(8-fluoro-5-methylchroman-6-yl)-4,7-dimethyl-
-3-oxoisoindolin-5-yl)-2-(tert-butoxy)acetic acid
##STR00028##
A solution of (S)-ethyl
2-((M)-2-benzyl-6-(8-fluoro-5-methylchroman-6-yl)-4,7-dimethyl-3-oxoisoin-
dolin-5-yl)-2-(tert-butoxy)acetate (30 mg, 0.052 mmol) in THF/EtOH
(1.5 mL, 2:1) was treated with LiOH (0.5 mL, 2.0 M) and heated to
65.degree. C. After 5 h, the reaction mixture was cooled to ambient
temperature and acidified with 1N HCl and extracted with EtOAc. The
organics were washed with brine, dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo. The residue was purified by reverse
phase HPLC to afford the title compound (13.4 mg) as a white solid.
.sup.1H NMR (400 MHz, METHANOL-d4) .delta.=7.42-7.28 (m, 5H), 6.64
(d, J=11.3 Hz, 1H), 5.12 (s, 1H), 4.83 (s, 2H), 4.28-4.23 (m, 4H),
2.90 (s, 3H), 2.74 (t, J=6.5 Hz, 2H), 2.13 (d, J=4.8 Hz, 2H), 1.83
(s, 3H), 1.81 (s, 3H), 1.12 (s, 9H); LC/MS (m/z) ES+=546 (M+1).
The following compounds were prepared in a manner similar to the
procedures described above for Examples 1-5.
Example 6:
(S)-2-(2-benzyl-6-(4,4-dimethylcyclohex-1-en-1-yl)-4,7-dimethyl-
-3-oxoisoindolin-5-yl)-2-(tert-butoxy)acetic acid
##STR00029##
The title compound was made in a similar manner as Example 5 except
using (4,4-dimethylcyclohex-1-en-1-yl)boronic acid in Step 7. 1H
NMR (400 MHz, METHANOL-d4) Shift=7.42-7.24 (m, 5H), 5.73-5.40 (m,
2H), 4.80 (s, 2H), 4.22 (s, 2H), 2.84 (d, J=2.8 Hz, 3H), 2.62-2.49
(m, 1H), 2.18-1.95 (m, 6H), 1.66-1.50 (m, 2H), 1.27-1.18 (m, 9H),
1.16-1.04 (m, 6H); LC/MS (m/z) ES+=490 (M+1).
Example 7:
(S)-2-((M)-2-benzyl-6-(8-fluoro-5-methyl-3,4-dihydro-2H-benzo[b-
][1,4]oxazin-6-yl)-4,7-dimethyl-3-oxoisoindolin-5-yl)-2-(tert-butoxy)aceti-
c acid
##STR00030##
The title compound was made in a similar manner as Example 5 except
using
8-fluoro-5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dih-
ydro-2H-benzo[b][1,4]oxazine (prepared from the known procedure
described in WO 2013/12649) in Step 7. 1H NMR (400 MHz,
CHLOROFORM-d) .delta.=7.41-7.28 (m, 5H), 6.27 (d, J=11.0 Hz, 1H),
5.19 (br. s., 1H), 4.90-4.73 (m, 2H), 4.35 (t, J=4.4 Hz, 2H), 4.14
(s, 2H), 3.57 (td, J=4.3, 6.7 Hz, 2H), 2.86 (s, 3H), 1.80 (s, 3H),
1.73 (s, 3H), 1.15 (s, 9H); LC/MS (m/z) ES+=547 (M+1).
Biological Examples
Anti-HIV Activity
MT4 Assay
Antiviral HIV activity and cytotoxicity values for compounds of the
invention from Table 1 were measured in parallel in the HTLV-1
transformed cell line MT-4 based on the method previously described
(Hazen et al., 2007, In vitro antiviral activity of the novel,
tyrosyl-based human immunodeficiency virus (HIV) type 1 protease
inhibitor brecanavir (GW640385) in combination with other
antiretrovirals and against a panel of protease inhibitor-resistant
HIV (Hazen et al., "In vitro antiviral activity of the novel,
tyrosyl-based human immunodeficiency virus (HIV) type 1 protease
inhibitor brecanavir (GW640385) in combination with other
antiretrovirals and against a panel of protease inhibitor-resistant
HIV", Antimicrob. Agents Chemother. 2007, 51: 3147-3154; and
Pauwels et al., "Sensitive and rapid assay on MT-4 cells for the
detection of antiviral compounds against the AIDS virus", J. of
Virological Methods 1987, 16: 171-185).
Luciferase activity was measured 96 hours later by adding a cell
titer glo (Promega, Madison, Wis.). Percent inhibition of cell
protection data was plotted relative to no compound control. Under
the same condition, cytotoxicity of the compounds was determined
using cell titer Glo.TM. (Promega, Madison, Wis.). IC50s were
determined from a 10 point dose response curve using 3-4-fold
serial dilution for each compound, which spans a concentration
range >1000 fold.
These values are plotted against the molar compound concentrations
using the standard four parameter logistic equation:
y=((Vmax*x^n)/(K^n+x^n))+Y2
where:
Y2=minimum y n=slope factor
Vmax=maximum y x=compound concentration [M]
K=EC50
When tested in the MT4 assay compounds were found to have IC.sub.50
values listed in Table 1.
TABLE-US-00001 TABLE 1 HIV MT4 Assay Example IC.sub.50 (uM) 1 0.025
2 0.042 3 0.086 4 0.052 5 0.005 6 0.036 7 0.014
* * * * *